Study IDs Protein That Inhibits HIV From Growing In Cell Cultures

How a harmless virus called GB Virus type C (GBV-C) protects against HIV infection is now better understood. Researchers at the Department of Veterans Affairs (VA) Iowa City Health Care System and the University of Iowa have identified a protein segment that strongly inhibits HIV from growing in cell models.

The team found that an 85-amino acid segment within a GBV-C viral protein called NS5A greatly slows down HIV from replicating in cells grown in labs. The study results will appear online this week in the Proceedings of the National Academy of Sciences.

The finding builds on earlier VA and UI work showing that people with HIV who also are infected GBV-C live longer than those infected only with HIV, said Jinhua Xiang, M.D., a VA research health scientific specialist, UI researcher and the current study's principal author.

GBV-C and its role in HIV infection have been studied for nearly a decade by Xiang, along with another study author Jack Stapleton, M.D., staff physician and researcher at the VA Iowa City Health Care System and professor of internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine.

"Identifying a specific protein made by GBV-C that inhibits HIV growth in cell culture strengthens the argument that GBV-C is responsible for the prolonged survival observed in several studies of HIV-positive people," Xiang said. "Understanding how the protein works may allow us to develop target-specific therapies that can mimic these effects and inhibit HIV.

"Potentially these novel therapies would have certain advantages over current drugs, as the newer therapies would target the cell in which HIV can replicate and not the virus directly. Therefore, HIV should have more difficulty developing resistance to the effects of this protein," Xiang added.

Xiang previously discovered that GBV-C grows in the same type of white blood cells, CD4 T-cells, that HIV grows in and ultimately destroys. HIV attaches to this T-cell by first landing on a receptor called CD4. Once it reacts with the receptor, HIV can enter the cell, multiply and destroy the T-cell, thereby causing immune deficiency.

"People with GBV-C have a slower rate of destruction of these T-cells," said Stapleton, who also is director of the Division of Infectious Diseases at the Iowa City VA and UI.

The current study shows that the newly identified protein, NS5A, inhibits HIV in part by decreasing the number of CD4 receptors available to HIV. With fewer places for HIV to "dock," less HIV enters the cells to inflict destruction.

However, Xiang cautioned, this is only part of the story, and the researchers must continue work to understand how the NS5A protein exerts its total effect.

"Before NS5A can be used for any kind of therapy, we need to further map it," Xiang said. "We need to zero in to see what region has the critical effect on HIV inhibition."

Once that is accomplished, the team will seek to develop small molecular drugs that mimic the inhibiting action.

Stapleton noted that GBV-C is not toxic to T-cells and is not associated with any human disease. As a result, the U.S. Food and Drug Administration does not require that blood donations be screened for this common virus.

Up to 3 percent of healthy blood donors in the United States have active GBV-C infection. An additional 12 percent have antibodies indicating past exposure at the time of donation. Because the GBV-virus is transmitted through bodily fluids, as is HIV, many HIV-positive individuals have evidence of past or present infection with GBV-C.

Stapleton and Xiang first began studying the GBV-C and HIV connection because they were skeptical of earlier studies published in the mid-1990s.

"It was a strange story," Stapleton said. "Who would have thought a virus floating around in a lot of people does not make them sick but could significantly influence survival in people with HIV?"

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